A primary goal of regenerative medicine is replacement of diseased or damaged cells and tissues. Abundant and safe sources of multipotent or pluripotent stem cells are necessary to further this goal. Embryonic stem (ES) cell lines are available for possible regenerative medicine applications, but challenges remain for their use, including possible immune rejection by a receiving patient (reviewed in Yabut et al., Aging 3(5):494-508, 2011). In recent years, induced pluripotence in differentiated cells has been explored as an alternative to ES cells (reviewed in Ebben et al., World Neurosurg. 76(3-4):270-275, 2011). It was discovered that expression of just four stem cell transcription factor genes (c-Myc, Sox2, Klf4, and Oct4) can de-differentiate and induce pluripotence in cells grown under particular culture conditions (e.g. in the absence of serum) (WO 2012/012708; and Takahashi et al., Cell. 126: 663-676, 2006). Among other benefits, such induced pluripotent stem (iPS) cells might be generated from a potential patient's own cells, thereby minimizing adverse immunoreactivity upon introduction of pluripotent or newly-differentiated cells to the patient.
iPS cells are currently produced by transforming cells with viral or other constitutive expression vectors encoding the four stem cell transcription factor genes. Among these, the over-expression of c-Myc is of particular concern because sustained Myc expression can result in malignant transformation. Furthermore, any of these vectors can permanently integrate into the cellular genome at sites that activate oncogenes or disrupt tumor suppressor genes. Current efforts in the stem cell field to produce iPS cells without the risk of malignant transformation involve identification of small molecules to induce individual stem cell genes (c-Myc, Sox2, Klf4, and Oct 4), with the goal of designing a mixture of several small molecules that together can produce iPS cells. But to date, no single agent has been identified that can be used to produce iPS cells. Thus, a continuing need exists to identify agents that can produce iPS cells, without the need for plasmid- or retroviral-mediated expression of individual stem cell-inducing genes.